A double-blind, randomized, placebo-controlled, multicenter, parallel group study to evaluate the efficacy, safety, and tolerability of macitentan in patients with idiopathic pulmonary fibrosis - MUSIC

• Register: EUCTR
• Last refreshed on: 12 June 2012
• Main ID: EUCTR2008-006054-17-SE
• Date of registration: 25/06/2009
• Prospective Registration: Yes
• Primary sponsor: Actelion Pharmaceuticals Ltd.
• Public title: A double-blind, randomized, placebo-controlled, multicenter, parallel group study to evaluate the efficacy, safety, and tolerability of macitentan in patients with idiopathic pulmonary fibrosis - MUSIC
• Scientific title: A double-blind, randomized, placebo-controlled, multicenter, parallel group study to evaluate the efficacy, safety, and tolerability of macitentan in patients with idiopathic pulmonary fibrosis - MUSIC
• Date of first enrolment: 12/08/2009
• Target sample size: 156
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-006054-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

France, Germany, Italy, Slovenia, Spain, Sweden

Key inclusion & exclusion criteria

Inclusion criteria:
1. Signed informed consent.
2. Male or female patients of at least 18 years of age (females of child-bearing potential must use a reliable method of contraception).
3. IPF diagnosis within 3 years prior to randomization, proven according to ATS/ERS consensus statement, with surgical lung biopsy.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Interstitial lung disease due to conditions other than IPF.
2. Presence of extensive HC on Baseline high-resolution computed tomography (HRCT) scan performed within 3 months prior to randomization.
The patient is not allowed in the study if HC involves more than 5% of the
parenchyma in 3 or more of the 6 zones (i.e., right and left lung, viewed at the levels
of tracheal carina, inferior pulmonary veins, and 1 cm above the dome of the
diaphragm), whether the involvement is unilateral or bilateral.
3. Severe concomitant illness limiting life expectancy (< 1 year).
4. Severe restrictive lung disease: FVC < 50% predicted (at both Visit 1 and Visit 2), or FVC < 1.2 liter.
5. Corrected diffusing capacity of the lung for carbon monoxide (corrected DLCO)
< 30% predicted (at both Visit 1 and Visit 2).
6. Residual volume = 120% predicted.
7. Obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.70.
8. Documented sustained improvement of the patient’s IPF condition up to 12 months
prior to randomization with or without IPF-specific therapy. The assessment of
sustained improvement will be left to the investigator’s judgment.
9. Recent pulmonary or upper respiratory tract infection (up to 4 weeks prior to
randomization).
10. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests [PFTs]).
11. Chronic heart failure with NYHA class III/IV or known left ventricular ejection
fraction < 25%.
12. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
13. Estimated creatinine clearance < 30 mL/min (see Appendix 2 for the calculation of
the estimated creatinine clearance).
14. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
> 1.5 × ULN.
15. Hemoglobin < 75% of the lower limit of the normal range.
16. Systolic blood pressure < 100 mmHg.
17. Pregnant or breast-feeding.
18. Current drug or alcohol dependence.
19. Chronic treatment with the following drugs (within 4 weeks of randomization):
• Oral corticosteroids (> 20 mg/day of prednisone or equivalent),
• Immunosuppressive or cytotoxic drugs including cyclophosphamide and
azathioprine,
• Antifibrotic drugs including pirfenidone, D-penicillamine, colchicine, TNFa
blocker, imatinib, interferon ?,
• Chronic use of N-acetylcysteine > 600 mg/day (prescribed for IPF).
• Oral anticoagulants prescribed for IPF.
20. Treatment with ERAs within 4 weeks prior to randomization.
21. Systemic treatment within 4 weeks prior to randomization with cyclosporine A or
tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin
[mTOR] inhibitors).
22. Treatment with CYP3A inducers within 4 weeks prior to randomization.
23. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
24. Planned treatment, or treatment, with another investigational drug within 4 weeks prior to randomization.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

To evaluate the efficacy, safety, and tolerabilitiy of macitentan in patients with idiopathic pulmonary fibrosis.
MedDRA version: 9.1 Level: LLT Classification code 10021240 Term: Idiopathic pulmonary fibrosis

Intervention(s)

Product Name: macitentan
Product Code: ACT-064992
Pharmaceutical Form: Tablet
INN or Proposed INN: macitentan
CAS Number: 441798-33-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: Secondary Objectives
•To evaluate the effect of macitentan on the time to disease worsening or death in patients with IPF.
•To evaluate the safety and tolerability of macitentan in this patient population.

Main Objective: Primary Objective
To demonstrate that macitentan positively affects the Forced Vital Capacity (FVC) in comparison with placebo in patients with idiopathic pulmonary fibrosis (IPF).

Primary end point(s): Primary Endpoint
Change from baseline to end of Period 1 in Forced Vital Capacity (FVC).
A mean difference from placebo of at least 0.1 liter is to be detected. This parameter is expected to be normally distributed with a standard deviation of 0.2 liter.
Secondary Endpoint
Time to occurrence of disease worsening or death up to EOS.
Disease worsening is defined as (i) worsening of PFTs or (ii) acute respiratory decompensation of IPF.
(i) Worsening of PFTs (confirmed by two tests at least 4 weeks apart) is defined as the occurrence of both:
? Decrease from baseline = 10% in FVC (absolute values, i.e., liters)
and
? Decrease from baseline = 15% in corrected DLCO (absolute values, i.e., ml•mmHg-1•min-1)
A patient unable to perform PFTs at a planned visit due to worsening of IPF will be considered as having a worsening of PFTs if this is not invalidated by a test at a follow-up visit.
(ii) Acute respiratory decompensation of IPF is defined as:
An unexplained rapid deterioration of patient’s condition within 4 weeks with an increasing shortness of breath requiring oxygen supplementation = 5 liters/min to maintain a resting SaO2 = 90% or PaO2 = 55 mmHg (sea level) or 50 mmHg (high altitude).
A documented acute respiratory decompensation of IPF will be considered to be an event, irrespective of the results of any follow-up PFTs or fatal outcome.
Patients who are transplanted (without a prior documented disease worsening), or who undergo a surgery/procedure that affects lung functions in a long-lasting and irreversible manner,or who withdraw their consent, or those lost to follow-up before the EOS will be censored.
Patients starting forbidden IPF medications (without prior documented disease worsening as defined above) will not be considered as having IPF worsening.
Exploratory endpoints
• Time to death (all causes) up to End-of-Study.
• Time to occurrence of disease worsening up to EOS.
• Proportion of patients who experienced either disease worsening or death at End-of-Period 1.
• Transition dyspnea index (TDI) at End-of-Period 1 and EOS.
• Proportion of patients who improve in TDI with at least 1 unit at End-of-Period 1 and EOS.
• Change from baseline to 4 months, 8 months, End-of-Period 1, EOT and EOS in PFTs (FEV1, FVC, DLCO).
• Change from Baseline to Month 4, End-of-Period 1, EOT and EOS in Quality of Life assessed by the SF-36 questionnaire (individual domains and summary component scores).
• Change from Baseline to Month 4, End-of-Period 1, EOT and EOS in the Composite Physiologic Index (CPI)

Secondary ID(s)

AC-055B201

2008-006054-17-DE